Lipoproteins regulation

Twelve reviews cover the structure, synthesis, and metabolism of lipoproteins, regulation of cholesterol synthesis, and the enzymes LCAT and lipoprotein lipase. 

The major enzymes involved in lipoprotein regulation are (Ij acyl-CoAxholesterol acyl-transferase (ACAT), which esterifies some cholesterol in the core of chylomicrons (2) lec-ithin cholesterol acyltransferase (LCAT), which esterifies cholesterol and helps transfer it to LDL (3) lipoprotein lipase (LPL), which hydrolyzes triglycerides to free fatty acids (FFA) and glycerol and (4) 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is essential in the synthesis of cholesterol and other steroids in the liver. 

Parhami F, Basseri B, Hwang J, Tintut Y, Demer LL. High-density lipoprotein regulates calcification of vascular cells. Circ Res 2002 91 570-576. 

We turn now to the biosynthesis of lipid structures. We begin with a discussion of the biosynthesis of fatty acids, stressing the basic pathways, additional means of elongation, mechanisms for the introduction of double bonds, and regulation of fatty acid synthesis. Sections then follow on the biosynthesis of glyc-erophospholipids, sphingolipids, eicosanoids, and cholesterol. The transport of lipids through the body in lipoprotein complexes is described, and the chapter closes with discussions of the biosynthesis of bile salts and steroid hormones. 

Figure22-10. Regulation of long-chain fatty acid oxidation in the liver. (FFA, free fatty acids VLDL, very low density lipoprotein.) Positive ( ) and negative ( ) regulatory effects are represented by broken arrows and substrate flow by solid arrows.

The reason for the cholesterol-lowering effect of polyunsaturated fatty acids is still not fully understood. It is clear, however, that one of the mechanisms involved is the up-regulation of LDL receptors by poly-and monounsaturated as compared with saturated fatty acids, causing an increase in the catabolic rate of LDL, the main atherogenic lipoprotein. In addition, saturated fatty acids cause the formation of smaller VLDL particles that contain relatively more cholesterol, and they are utilized by extrahepatic tissues at a slower rate than are larger particles—tendencies that may be regarded as atherogenic. 

As an example, the low-density lipoprotein (LDL) molecule and its receptor (Chapter 25) are internalized by means of coated pits containing the LDL receptor. These endocytotic vesicles containing LDL and its receptor fuse to lysosomes in the cell. The receptor is released and recycled back to the cell surface membrane, but the apoprotein of LDL is degraded and the choles-teryl esters metabolized. Synthesis of the LDL receptor is regulated by secondary or tertiary consequences of pinocytosis, eg, by metabolic products—such as choles-... 

Using human hepatoma-derived cell lines Kong et al. [268] showed that berberine increased mRNA and protein as well as the function of hepatic linear low density lipoprotein receptor (LDLR). It does not stimulate the transcription of LDLR, as the LDLR promoter activity was not increased by this compound. Post-transcriptional regulation appears to be the main working mechanism underlying the effect of this alkaloid on LDLR expression. It was proposed that berberine can be used as a monotherapy to treat hypercholes-terolemic patients [268]. Very recently it was observed [269] that berberine reduces cholesterol and Upid accumulations in plasma as well as Uver. 

Kayden, H.J. andTraber, M.G. (1993). Absorption, lipoprotein transport and regulation of plasma concentrations of vitamin E in humans. J. Lipid Res. 34, 343-358. 

Despite the feasibility of using cultured RPE cells for studies similar to those performed using Caco-2 cells, the role of the RPE in carotenoid uptake and dynamic regulation has only just begun to be investigated. As carotenoids are carried in blood by lipoproteins, lipoprotein-rich serum seems to be the most appropriate vehicle for carotenoid delivery to cultured RPE cells. Indeed, recent studies comparing carotenoid delivery from fetal calf serum and from organic solvents showed that delivery in the presence of serum was superior to tetrahydrofuran (Shafaa et al., 2007). 

Peroxisome-proliferator activated receptors (PPARs) are lipid-activated transcription factors exerting several functions in development and metabolism. PPARa is implicated in the regulation of lipid metabolism, lipoprotein synthesis, and inflammatory response in liver and other tissues. 

Cohen JC. Contribution of cholesterol 7alpha-hydroxylase to the regulation of lipoprotein metabolism. Curr Opin Lipidol 1999 10 303-307. 

Fruchart JC, Duriez P, Staels B. Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis. Curr Opin Lipidol 1999 10 245-257. 

Salleh MN, Runnie I, Roach, PD, Mohamed S and Abeywardena MY. 2002. Inhibition of low-density lipoprotein oxidation and up-regulation of low-density lipoprotein receptor in HepG2 cells by tropical plant extracts. J Agric Food Chem 50(13) 3693-3697. 

The bulk of pinocytosis in the nervous system is mediated by clathrin-mediated endocytosis (CME) [55] and this is the best-characterized pathway. More detail about clathrin-mediated pathways will be given when receptor-mediated endocytosis and the synaptic vesicle cycle pathways are considered. Pinocytosis through CME is responsible for uptake of essential nutrients such as cholesterol bound to low density lipoprotein (LDL) and transferring, but also plays a role in regulating the levels of membrane pumps and channels in neurons. Finally, CME is critical for normal synaptic vesicle recycling. 

These findings led to the conclusion that the regulation of membrane anchored proteins has to be achieved by mechanisms other than spontaneous dissociation. In principal, binding to an escort protein or de-S-acylation may induce dissociation of the lipoproteins out of the membrane structure. 

---